EP0008802A1

EP0008802A1 - Ergoline derivatives, their preparation and therapeutic composition containing them

Info

Publication number: EP0008802A1
Application number: EP79103357A
Authority: EP
Inventors: Sergio Mantegani; Giuliana Dr. Biolog. Arcari; Anna Maria Caravaggi; Germano Via De Santis 23/B Bosisio
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1978-09-08
Filing date: 1979-09-07
Publication date: 1980-03-19
Also published as: AU526764B2; FI66613C; US4321381A; YU41347B; HU179450B; FI66613B; IL58182A; JPS5589282A; IE48550B1; CA1128502A; CS208135B2; FI792776A; EP0008802B1; ZA794682B; AU5045579A; YU217479A; DK148419B; SU906377A3; GR71867B; DK375279A

Abstract

The novel ergoline derivatives of the general formula I <CHEM> wherein R1 represents an ally or alkoxy group having from 1 to 4 carbon atoms, phenyl, a 5- or 6-membered heterocyclic ring which is preferably saturated, an amino group, a substituted amino group of the formula NHR min (wherein R min represents an alkyl group having from 1 to 4 carbona toms, a cycloalkyl group, a benzyl group or a phenyl group), or a substituted amino group of the formula NR sec R''' (wherein R sec and R''' both represent alkyl groups having from 1 to 4 carbon atoms); R2 represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms or a phenyl group; R3 represents a halogen atom, a cyano group, a halogenated lower alkyl group, methylthio, methylsulfonyl or sulfonamido group, an alkoxy group having from 1 to 4 carbon atoms, an acyl group, having from 2 to 5 carbon atoms or a benzoyl group; R4 represents a hydrocarbon group having from 1 to 4 carbon atoms; R<5> represents a hydrogen atom or a methoxy group; R6 is hydrogen, a halogen atom or a methyl group; R7 is hydrogen or a methyl group; and the pharmaceutically acceptable addition salts with organic or inorganic acids thereof exhibit antihypertensive and antiprolactinic activity. Their preparation is described, e.g. 2-cyano3- (6 min -methyl-ergoline-8 min beta )-propionic acid ethyl ester is obtained by reacting sodium ethyl cyanoacetate with 6-methyl-8 beta -tosyloxymethylergoline.

Description

The invention relates to ergot derivatives, a process of preparing same and therapeutic composition.
The ergoline derivatives according to the invention are of the general formula I:
wherein R₁ represents an alkyl or alkoxy group having from 1 to 4 carbon atoms, phenyl, a 5- or 6-membered heterocyclic ring which is preferably saturated, an amino group, a substituted amino group of the formula NHR' (wherein R' represents an alkyl group having from 1 to 4 carbon atoms, a cycloalkyl group, a benzyl group or a phenyl group), or a substituted amino group of the formula NR"R"' (wherein R" and R"' both represent alkyl groups having from 1 to 4 carbon atoms);

R₂ represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms or a phenyl group;
R₃ represents a halogen atom, a cyano group, a halogenated lower alkyi group, methylthio, methylsulfonyl or sulfonamido group, an alkoxy group having from 1 to 4 carbon atoms, an acyl group having from 2 to 5 carbon atoms or a benzoyl group;
R₄ represents a hydrocarbon group having from 1 to 4 carbon atoms;
R₅ represents a hydrogen atom or a methoxy group;
R₆ is hydrogen, a halogen atom or a methyl group;
R₇ is hydrogen or a methyl group, and the pharmaceutically acceptable addition salts with organic or inorganic acids thereof.

According to the embodiment of the invention wherein R₁ is alkyl, this is preferably the methyl group. When R₁ is a 5- or 6-membered heterocycle, this can advantageously be the piperidino, 1-pyrrolidinyl, morpholino or the 4-methyl-1-piperazinyl group.
Further in the general formula the terms "halogen" and "halogenated lower alkyl group" should be construed to preferably encompass the fluorine atom, the difluoromethyl, difluorobromomethyl and the trifluoromethyl group.
Ergoline derivatives of the general formula I as above defined may be prepared by condensing a compound of the general formula II below with an alkaline salt of a compound of the general formula III below.
In the general formulae II and III R₁, R₂, ^R ₃, R₄, R₅, R₆ and R₇ have the meanings given above.
The condensation, which is a process within the scope of the invention, may be carried out in a polar aprotic solvent, suitable temperatures are in the range from 50 to 100°C and the reaction is usually terminated after 2 to 10 hours. Suitable polar aprotic solvents are dimethylsulfoxide, dimethylformamide, hexamethylphosphotriamide and the like. The condensation is preferably carried out in the presence of sodium or potassium iodide. The condensation products may be purified by conventional procedures. Chromatography over silicagel is especially suitable.
Compounds according to the invention are useful as anti- hypertensive agents and also have moderate to good antiprolactinic activity. They can be used as an active ingredient in a therapeutical composition along with usual pharmaceutically acceptable additives.

Evaluation of anti-hypertensive activity

1. Spontaneously hypertensive rat (MHS)

Four spontaneously hypertensive male rats strain MHS weighing 250-300 g for each group were used. Animals were treated for four consecutive days. Drugs were administered by gastric gavage, suspended in 5% arabic gum (0,2 ml/ 100 g body weight) and blood pressure (BP) and heart rate (HR) were measured at the tail by BP Recorder W + W. Blood pressure and heart rate were measured on the first and fourth day of treatment 1 hour before and 1 and 5 hours after drug administration.
Results are reported in tables 1 and 2.

2. Normotensive rat (NR)

Blood pressure recordings have been made in conscious normotensive unrestrained rats weighing approximately 300g, via a catheter chronically inserted into the left common carotid artery. Implantation of arterial cannula was made under sodium pentobarbital anaesthesia (50 mg/kg i.p.).
A 1 cm long incision was made through the previously shaved ventral surface of the neck and the tissues overlying the trachea parted by blunt dissection to reveal the carotid artery. The polyethylene catheter used was made with PE 50 tubing, previously filled with saline containing 250 I.U./ml heparin. The tip of the cannula was pushed at least 2 cm inside the vessel toward the heart. The cannula was then firmly tied and passed beneath the skin to emerge from a small incision in the back of the neck. During the postoperative period and before the start of each recording session, the cannula was flushed through daily with saline containing heparin (250 I.U./ml). The experiments were performed two days after surgery. Drugs were administered by gastric gavage. Results are reported in Tables 3 and 4.

Evaluation of the toxicity (LD₅₀)

Ten male mice for each group were orally treated with drugs at different dose levels for the determination of lethal dose 50 (LD₅₀). Mice were observed for seven days after administration. LD₅₀'s are summarized in Table 5.
From the data reported in table 1 it is apparent that compounds according to the invention induce a consistent blood pressure fall in spontaneously hypertensive rats both at 2 and 5 mg/kg os. This reduction of the blood pressure appears not only on the first day of treatment but also on the fourth day showing absence of tachyphylaxis. Moreover the reduction lasts 5 hours at least. When compared with hydralazine and o6-methyl-DOPA, two known antihypertensive drugs, the new compounds, at the 2 mg/kg level, are more active than hydralazine and more than 15 fold as active as α-methyl-DOPA. At 5 mg/kg level the new compounds are more active than hydralazine, particularly on the fourth day, and more than 20 fold as active as α-methyl-DOPA. When the variation of the heart rate (HR) is considered, it can be seen (table 2) that the new compounds induce only minor variations whereas d-methyl-DOPA greatly increases it, particularly at the 5 mg/kg level.
The results obtained in the incannulated normotensive rat (table 3) confirm the antihypertensive activity of the new compounds which compares favourably with that of hydralazine. Moreover the variations of the heart rate (table 4) are limited and in any case a favourable reduction rather than an unfavourable increase in the heart rate is observed. Finally the toxicity of the new compounds, expressed as LD₅₀ (table 5), is no greater than that of hydralazine, being in many cases largely inferior and when the therapeutic ratio (activity versus toxicity) is considered, the new compounds result also largely better antihypertensive agents than α-methyl-DOPA

Example 1

2-Cyano-3-(6'-methylergoline-8'ß)-propionic acid ethyl ester (I: R₁ = OCH₂CH₃, R₃ = CN, R₄ ⁼ CH₃, ^R ₂ ^{= R} ₅ ^{= R} ₆ ^{= R} ₇ ^{= H}) A mixture of 16.9 g of sodium ethyl cyanoacetate, 41 g of 6-methyl-8B-tosyloxymethylergoline and 16 g of potassium iodide in 250 ml of dimethylsulfoxide and 50 ml of ethyl cyanoacetate was heated under stirring at 70°C for 5 hours. The solution was poured into 7 litres of iced water, and the resultant precipitate was filtered off, dried and chromatographed on a silicagel column, using chloroform as eluent, to give 24 g of the title compound, m. p. 200-202°C.

Example 2

2-Cyano-3-(6'-methylergoline-8'ß)-N-propionylmorpholine

(I: R₁ = morpholino, R₃ ⁼ CN, R₄ ^{= C}H₃, R₂ ^{= R} ₅ ⁼ R₆ = ^R ₇= H)
A mixture of 0.85 g of sodium cyanoacetylmorpholine, 2 g of 6-methyl-8ß-tosyloxymethylergoline, 0.6 g of sodium iodide in 10 ml of dimethylsulfoxide and 2 g of cyanoacetylmorpholine was heated under stirring at 80°C for 10 hours. The solution was poured into 500 ml of water and the resultant precipitate was filtered off, dried and chromatographed over silicagel to give 1.7 g of the title compound, m. p. 220-221°C.

Example 3

2-Cyano-3-(6'-methylergoline-8'ß)-N-phenylpropionamide

(I: R₁ = anilino, R₃= CN, R₄ ⁼ CH₃, R₂ = ^R ₅ ^{= R} ₆ ⁼ R₇ = H)
Operating as in example 2, but employing sodium cyanoacetanilide, 2-cyano-3-(6-methylergoline-8ß)-N-phenylpropion- amide, m. p. 180-181°C, was obtained in 60 % yield.

Example 4

2-Cyano-3-(6^1-methylergoline-8¹B)-N-propionyl-(N'-methyl)-piperazine

(_I: R₁ = 4-methyl-1-piperazinyl, R₃ = CN, R₄ ⁼ CH_3' R₂ = R₅ = R₆ ⁼ R₇= H)
Operating as in example 2, but employing sodium cyanoacetyl-N-methyl-piperazine, the title compound, m. p. 206-207°C, was obtained in 60 % yield.

Example 5

2-Cyano-3-(6'-methylergoline-8'ß)-N-ethylpropionamide (355/1138)

(I: R₁ = CH₃CH₂NH, R₃ ⁼ CN, R₄ ⁼ CH₃, R₂ = R₅ = R₆ = R₇ = H)
Operating as in example 2, but employing sodium N-ethylcyanoacetamide, the title compound, m. p. 225-226°C, was obtained in 65 % yield.

Example 6

2-Cyano-3-(6'-methylergoline-8'ß)-N-benzylpropionamide (355/1131)

(I: R₁ = C₆H₅CH₂N^H, R₃ ⁼ CN, R₄ ⁼ CH₃, R₂ = ^R ₅ ⁼ R₆ = R₇ = _H)
Operating as in example 2, but employing sodium N-benzyl- cyanoacetamide, the title compound, m. p. 233-234°C, was obtained in 75 % yield.

Example 7

2-Cyano-3-(6'-methylergoline-8'ß)-N-propionylpiperidine

(I: R₁ = piperidino, R₃ = CN, R₄ ^{= CH} ₃, ^R ₂ ^{= R} ₅ ^{= R} ₆ ⁼ R₇ = H)
Operating as in example 2, but employing sodium cyano- acetylpiperidine, the title compound, m.p. 252-253°C, was obtained in 77 % yield.

Example 8

2-Cyano-3-(6'-methylergoline-8'ß)-propionamide (355/1057) (I: R₁ = NH₂, R₃ ⁼C^{N, R} ₄ ^{= CH} ₃, ^R ₂ ^{= R} ₅ ^{= R} ₆ ^{= R} ₇ ^{= H})

Operating as in example 2, but employing sodium cyano- acetamide, the title compound, m. p. 248-250°C, was obtained in 45 % yield.

Example 9

2-Cyano-3-(6'-ethylergoline-8'ß)-propionamide

(I: R₁ = NH₂, R₃ = ^{CN, R} ₄ ⁼ C₂H₅, ^R ₂ ^{= R} ₅ ^{= R} ₆ ^{= R} ₇ ^{= H})
Operating as in example 8, but-employing 6-ethyl-8B-tosyloxymethylergoline, the title compound was obtained in 42 % yield, m. p. 243-245°C

Example 10

2-Cyano-3-(6'-allylergoline-8'B)-propionamide

(I: R₁ ⁼ NH₂, ^R ₃ ^{= CN, R} ₄ ⁼ allyl, ^R ₂ ^{= R} ₅ ^{= R} ₆ ^{= R} ₇ ^{= H})
Operating as in example 8, but employing 6-allyl-8B-tosyl- oxymethylergoline, the title compound was obtained in 40 % yield.

Example 11

2-Cyano-3-(6'-methylergoline-8'ß)-N-propionylpyrrolidine (355/1133)

(I: R₁ = 1-pyrrolidinyl, R₃ = CN, R₄ ⁼ CH₃, R2 ^{= R} ₅ ^{= R} ₆ ⁼ R₇ = H)
Operating as in example 2, but employing sodium cyano- acetylpyrrolidine, the title compound, m. p. 219-220°C, was obtained in 68 % yield.

Example 12

2-Cyano-3-(1',6'-dimethylergoline-8'ß)-propionamide

(I: R₁ = NH₂, R₃ ⁼ CN, R₄ ^{= R} ₇ ⁼ CH₃, R₂ = ^R ₅ ^{= R} ₆ ^{= H})
Operating as in example 8, but employing 1,6-dimethyl-8ß-tosyloxymethylergoline, the title compound, m. p. 196-197°C, was obtained in 80 % yield.

Example 13

2-Cyano-3-(6'-methyl-10'-methoxyergoline-8'β)-propionamide

(I: R₁= NH₂, R3 ⁼ CN, R₄ ⁼ CH₃, R₅ ⁼ CH₃O, R₂ = R₆ = R₇= H)
Operating as in example 8, but employing 6-methyl-10-methoxy-8β-tosyloxymethylergoline, the title compound, m. p. 207-208°C, was obtained in 45 % yield.

Example 14

2-Cyano-3-{1',6'-dimethyl-10'-methoxyergoline-8'β)-propion- amide

(I: R₁= NH₂, R3 = C^N, R₄= ^R ₇ ⁼ CH₃, R₅= CH₃O, R₂ = R₆ = H)
Operating as in example 8, but employing 1,6-dimethyl-10-methoxy-8β-tosyloxymethylergoline, the title compound, m. p. 190-192°C, was obtained in 81 % yield.

Example 15

2-Cyano-3-(2'-bromo-6'-methylergoline-8'β)-propionamide (355/1139)

(I: R₁= NH₂, R₃ = CN, R₄ = CH₃, R₆= Br, R₂ = R₅ = R₇ = H)
Operating as in example 8, but employing 2-bromo-6-methyl-8β-tosyloxymethylergoline, the title compound, m. p. 171-173°C, was obtained in 41 % yield.

Example 16

2-Acetyl-3-(5'-methylergoline-8'β)-propionic acid ethyl ester

(I: R₁ = OCH₂CH₃, R₃ ⁼ CH₃CO, R₄= CH₃, R₂= R₅ ⁼ R₆ = R₇= H)
Operating as in example 1, but employing sodium ethyl acetoacetate, the title compound, m. p. 178-179°C, was obtained in 70 % yield.

Example 17

3-Acetyl-4-(6'-methylergoline-8'β)-butanone

(I: R₁ = R₄ = CH₃, R₃ = CH₃CO, R₂ = R₅ = R₆ = R₇ = H)
Operating as in example 1, but employing sodium acetylacetone, the title compound, m. p. 210-212°C, was obtained in 75 % yield.

Example 18

2-Cyano-2-ethyl-3-(6'-methylergoline-8'β)-propionamide

(I: R₁ = NH₂, R₂= C₂H₅, R₃= CN, R₄= CH₃, R₅= R₆= ^R ₇ ⁼ H) Operating as in example 8, but employing sodium ethylcyanoacetamide, the title compound, m. p. 217°C, was obtained in 43 % yield.

Example 19

2-Cyano-2-phenyl-3-(6'-methylergoline-8'β)-propionamide

(I: R₁ = NH₂, R₂ = C₆H₅, R₃ = CN, R₄ = CH₃, R₅ = R₆ = ^R ₇ ⁼H)
Operating as in example 8, but employing sodium phenyl- cyanoacetamide, the title compound, m. p. 232°C, was obtained in 45 % yield.

Example 20

2-Cyano-3-(1',6'-dimethylergoline-8'β)-N-ethylpropionamide

Operating as in example 5, but employing 1,6-dimethyl-8B-tosyloxymethylergoline, the title compound, m. p. 194-196°C, was obtained in 60 % yield.

Example 21

2-Cyano-3-(1',6'-dimethylergoline-8'β)-N-propionylpyrroli- dine

Operating as in example 11, but employing 1,6-dimethyl-8B-tosyloxymethylergoline, the title compound, m. p. 207-209°C, was obtained in 55 % yield.

Example 22

2-Cyano-3-(1',6'-dimethylergoline-8'β)-N-benzylpropionamide

Operating as in example 6, but employing 1,6-dimethyl-8β-tosyloxymethylergoline, the title compound, m. p. 175-177°C, was obtained in 40 % yield.

Example 23

2-Methylsulfonyl-3-(6'-methylergoline-8'β)-propionic acid ethyl ester

Operating as in example 1, but employing sodium ethyl- methylsulfonylacetate, the title compound, m. p. 199-201°C, was obtained in 70 % yield.

Example 24

2-Methylsulfonyl-3-(6'-methylergoline-8'β)-N-benzylpropion- amide

Operating as in example 2, but employing sodium N-benzyl-methyl- sulfonylacetamide, the title compound, m. p. 285-287°C, was obtained in 60 % yield.

Example 25

2-Methylsulfonyl-3-(6^1-methylergoline-8'B)-propionamide

Operating as in example 2, but employing sodium methyl- sulfonylacetamide, the title compound, m. p. 242-244°C, was obtained in 65 % yield.

Example 26

2-Methylsulfonyl-3-(6'-methylergoline-8'β)-N-propionyl- pyrrolidine

Operating as in example 2, but employing sodium methyl- sulfonylacetylpyrrolidine, the title compound, m. p. 135-237°C, was obtained in 69 % yield.

Example 27

2-Methylsulfonyl-3-(6^1-methylergoline-8¹8)-N-ethylpropion- amide

Operating as in example 2, but employing sodium N-ethyl- methylsulfonylacetamide, the title compound, m. p. 227-229°C, was obtained in 60 % yield.

Example 28

2-Acetyl-3-(6'-methylergoline-8'B)-propionamide

Operating as in example 2, but employing sodium acetyl- acetamide, the title compound, m. p. 225-227°C, was obtained in 40 % yield.

Example 29

2-Cyano-3-(2'-chloro-6'-methylergoline-8'B)-propionamide

Operating as in example 8, but employing 2-chloro-6-methyl-8β-tosyloxymethylergoline, the title compound, m. p. 245-246°C, was obtained in 45 % yield.

Claims

1. A compound of the general formula I

wherein R₁ represents an alkyl or alkoxy group having from 1 to 4 carbon atoms, phenyl, a 5- or 6-membered heterocyclic ring which is preferably saturated, an amino group, a substituted amino group of the formula NHR' (wherein R' represents an alkyl group having from 1 to 4 carbon atoms, a cycloalkyl group, a benzyl group or a phenyl group), or a substituted amino group of the formula NR"R"' (wherein R" and R"' both represent alkyl groups having from 1 to 4 carbon atoms);

R₂ represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms or a phenyl group;

R₃ represents a halogen atom, a cyano group, a halogenated lower alkyl group, methylthio, methylsulfonyl or sulfonamido group, an alkoxy group having from 1 to 4 carbon atoms, an acyl group having from 2 to 5 carbon atoms or a benzoyl group;

R₄ represents a hydrocarbon group having from 1 to 4 carbon atoms;

R₅ represents a hydrogen atom or a methoxy group;

R₆is hydrogen, a halogen atom or a methyl group;

R₇ is hydrogen or a methyl group; and the pharmaceutically acceptable addition salts with organic or inorganic acids thereof.

2. A compound according to claim 1, wherein R₁ is a methyl group.

3. A compound according to claim 1 or 2, wherein R_i is the piperidino, 1-pyrrolidinyl, morpholino or 4-methyl-1-piperazinyl group.

4. A compound according to claim 1, 2 or 3, wherein R₃ is selected from the group consisting of a fluorine atom, difluoromethyl, difluorobromomethyl and a trifluoromethyl group.

5. A process for the preparation of a compound of general formula I, as difined in claims 1 to 4, which comprises condensing a suitable intermediate of formula II:

wherein R₄, R₅, R₆ and R₇ have the meanings given in claim 1, with an alkaline salt of a compound of formula III:

wherein R₁, R₂, R₃have the meanings already given in claim 1, and, if desired, adding of organic or inorganic acid to obtain the addition salt.

6. A process according to claim 5, wherein the condensation is carried out in a polar aprotic solvent, such as dimethylsulfoxide, dimethylformamide, hexamethylphosphotriamide.

7. A process according to claim 6, wherein the condensation is carried out in the presence of sodium iodide, and at a temperature of 50-100°C for 2 to 10 hours, whereafter the resulting raw product is purified by chromatography on silicagel.

8. A therapeutical composition containing at least one compound according to claims 1 to 4 as active ingredient along with usual pharmaceutically acceptable additives.